Desensitization of guinea pig left atria to the inotropic effects of glucagon was produced in vitro by treatment of the atria with 10(-6) M glucagon for 2 or 15 min. Desensitization of the contractile response was associated with a loss of the ability of glucagon to elevate cyclic AMP levels. A highly significant correlation was found between the increase in contractile force and the increase in cyclic AMP levels in control and glucagon desensitized left atria.